Repeatedly exposing rats to drugs such as amphetamine (AMPH) can lead to enhanced locomotor responding, nucleus accumbens (NAcc) dopamine (DA) overflow and drug taking when rats are re-exposed to the drug weeks to months later. These phenomena, manifestations of sensitization, may play an important role in the transition from casual drug use to abuse. Unraveling the neuroadaptations that underlie the expression of sensitization-enhanced behavioral and neurochemical responding to the drug-- may help identify targets for therapeutic intervention. One of many proteins that play an important role in mediating signaling cascades underlying the expression of sensitization is calcium/calmodulin-dependent protein kinase II (CaMKII). While acute AMPH-induced locomotor responding and NAcc DA release are calcium-independent, sensitized locomotion and DA release are calcium and CaMKII-dependent. In addition, striatal slices from rats exposed to repeated, intermittent injections of AMPH show enhanced calmodulin levels and increased CaMKII activity compared to those obtained from saline-exposed controls. We hypothesize that using viral-mediated gene transfer to modify CaMKII levels in the NAcc will alter behavioral responding to AMPH. The experiments proposed in this grant application will test two main hypotheses. Hypothesis 1: Increasing levels of CaMKII in the NAcc will enhance locomotor responding to a low, threshold dose of AMPH and enhance self-administration of the drug, effects similar to those observed in rats exposed to a sensitizing drug regimen. Rats will be surgically implanted with bilateral guide cannulae and intravenous catheters. Microinjections of the viral vectors will then be made and locomotor and self- administration experiments will be conducted to determine how this manipulation alters sensitivity to AMPH. The efficacy of viral-mediated gene transfer will be determined using immunoblotting. Hypothesis 2: Increasing levels of an inactive mutant form of CaMKII in the NAcc of sensitized rats will diminish enhanced AMPH self-administration observed in these rats. Rats will be exposed to repeated, intermittent injections of AMPH followed by a withdrawal period, during which the animals will be surgically prepared. Following a period of drug self-administration, microinjections of the viral vectors will be made and the effect of this manipulation on drug self-administration subsequently assessed. Using an animal model of addiction is an effective way to study the transition form casual to compulsive drug use. This research will contribute to the ultimate goal of preventing drug addiction by investigating ways to prevent the enhanced drug taking observed in rats that have been previously exposed to AMPH. [unreadable] [unreadable] [unreadable]